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Depression: HELP
Articles by Richard C. Shelton
Based on 60 articles published since 2010
(Why 60 articles?)
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Between 2010 and 2020, Richard Shelton wrote the following 60 articles about Depression.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial The Course of Illness After Initial Diagnosis of Major Depression. 2016

Shelton, Richard C. ·Department of Psychiatry and Behavioral Neurobiology, The University of Alabama at Birmingham. ·JAMA Psychiatry · Pubmed #26934634.

ABSTRACT: -- No abstract --

2 Editorial Does concomitant use of NSAIDs reduce the effectiveness of antidepressants? 2012

Shelton, Richard C. · ·Am J Psychiatry · Pubmed #23032377.

ABSTRACT: -- No abstract --

3 Review Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: A systematic review and meta-analysis. 2018

Wang, Qingzhong / Shelton, Richard C / Dwivedi, Yogesh. ·Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: ydwivedi@uab.edu. ·J Affect Disord · Pubmed #28850857.

ABSTRACT: BACKGROUND: Gene-environment interaction contributes to the risks of psychiatric disorders. Interactions between FKBP5 gene variants and early-life stress may enhance the risk not only for mood disorder, but also for a number of other behavioral phenotypes. The aim of the present study was to review and conduct a meta-analysis on the results from published studies examining interaction between FKBP5 gene variants and early-life stress and their associations with stress-related disorders such as major depression and PTSD. METHODS: A literature search was conducted using PsychINFO and PubMed databases until May 2017. A total of 14 studies with a pooled total of 15109 participants met the inclusion criteria, the results of which were combined and a meta-analysis was performed using the differences in correlations as the effect measure. Based on literature, rs1360780, rs3800373, and rs9470080 SNPs were selected within the FKBP5 gene and systematic review was conducted. RESULTS: Based on the Comprehensive Meta-Analysis software, no publication bias was detected. Sensitivity analysis and credibility of meta-analysis results also indicated that the analyses were stable. The meta-analysis showed that individuals who carry T allele of rs1360780, C-allele of rs3800373 or T-allele of rs9470080 exposed to early-life trauma had higher risks for depression or PTSD. LIMITATIONS: The effects of ethnicity, age, sex, and different stress measures were not examined due to limited sample size. CONCLUSIONS: These results provide strong evidence of interactions between FKBP5 genotypes and early-life stress, which could pose a significant risk factor for stress-associated disorders such as major depression and PTSD.

4 Review Treatment resistant depression: strategies for primary care. 2013

Preston, Taylor C / Shelton, Richard C. ·Department of Psychiatry and Behavioral Neurobiology, The University of Alabama at Birmingham, SC 1026 1720 2nd Ave S, Birmingham, AL 35294-0018, USA. ·Curr Psychiatry Rep · Pubmed #23712721.

ABSTRACT: Depression is commonly diagnosed and treated in primary care. Recent evidence indicates that the majority of depressed patients will not fully recover with an initial antidepressant treatment. This paper reviews commonly used options for treatment after an inadequate initial antidepressant response. The alternatives range widely, and include escalating the dose of the initial antidepressant, switching to an alternative medication, combining two antidepressants with different mechanisms of action (e.g., bupropion + SSRI or mirtazapine + venlafaxine), adding other medications such as lithium or certain atypical antipsychotics (olanzapine, aripiprazole, or quetiapine) to the antidepressant, adding a natural product such as l-methylfolate or s-adenosylmethionine (SAMe), or adding cognitive behavioral psychotherapy. What agent to be used will depend on the comfort level of the primary care practitioner and the availability of Psychiatry referral. However, it is reasonable to take one or more additional steps to attempt to achieve remission.

5 Clinical Trial Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. 2019

Popova, Vanina / Daly, Ella J / Trivedi, Madhukar / Cooper, Kimberly / Lane, Rosanne / Lim, Pilar / Mazzucco, Christine / Hough, David / Thase, Michael E / Shelton, Richard C / Molero, Patricio / Vieta, Eduard / Bajbouj, Malek / Manji, Husseini / Drevets, Wayne C / Singh, Jaskaran B. ·Janssen Research and Development, Beerse, Belgium (Popova) · Janssen Research and Development, Titusville, N.J. (Daly, Lane, Lim, Hough, Manji, Drevets) · the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas (Trivedi) · Janssen Research and Development, Spring House, Pa. (Cooper) · Janssen Canada, Toronto (Mazzucco) · the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia (Thase) · the Department of Psychiatry, University of Alabama School of Medicine, Birmingham (Shelton) · Clínica Universidad de Navarra, Pamplona, Spain (Molero) · Institute of Neuroscience, University of Barcelona, Hospital Clinic, IDIBAPS, CIBERSAM, Barcelona, Spain (Vieta) · Charité Universitätsmedizin Berlin, Berlin (Bajbouj) · Janssen Research and Development, San Diego (Singh). ·Am J Psychiatry · Pubmed #31109201.

ABSTRACT: OBJECTIVE: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray. METHODS: This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures. RESULTS: Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing. CONCLUSIONS: Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.

6 Clinical Trial Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. 2018

Daly, Ella J / Singh, Jaskaran B / Fedgchin, Maggie / Cooper, Kimberly / Lim, Pilar / Shelton, Richard C / Thase, Michael E / Winokur, Andrew / Van Nueten, Luc / Manji, Husseini / Drevets, Wayne C. ·Department of Neuroscience, Janssen Research & Development LLC, Titusville, New Jersey. · Department of Neuroscience, Janssen Research & Development LLC, San Diego, California. · Department of Neuroscience, Janssen Research & Development LLC, Spring House, Pennsylvania. · Department of Quantitative Sciences, Janssen Research & Development LLC, Titusville, New Jersey. · Department of Psychiatry, University of Alabama School of Medicine, Birmingham. · Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia. · Institute of Living, Hartford, Connecticut. · Department of Psychiatry, UConn Health, Farmington, Connecticut. · Department of Neuroscience, Janssen Research & Development, Beerse, Belgium. ·JAMA Psychiatry · Pubmed #29282469.

ABSTRACT: Importance: Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. Objective: To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). Design, Setting, and Participants: This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. Interventions: In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. Main Outcomes and Measures: The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Results: Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: -4.2 [2.09], P = .02; 56 mg: -6.3 [2.07], P = .001; 84 mg: -9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (-7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy). Conclusions and Relevance: In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials. Trial Registration: clinicaltrials.gov identifier: NCT01998958.

7 Clinical Trial A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. 2016

Singh, Jaskaran B / Fedgchin, Maggie / Daly, Ella J / De Boer, Peter / Cooper, Kimberly / Lim, Pilar / Pinter, Christine / Murrough, James W / Sanacora, Gerard / Shelton, Richard C / Kurian, Benji / Winokur, Andrew / Fava, Maurizio / Manji, Husseini / Drevets, Wayne C / Van Nueten, Luc. ·From Janssen Research and Development, Titusville, N.J., and Beerse, Belgium; the Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, N.Y.; the Department of Psychiatry, Yale University, New Haven, Conn.; the Department of Psychiatry and Behavioral Neurobiology, School of Medicine, University of Alabama at Birmingham; the Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas; the Institute of Living, Hartford, Conn.; University of Connecticut Health Center, Farmington; the Department of Psychiatry, Massachusetts General Hospital, Boston. ·Am J Psychiatry · Pubmed #27056608.

ABSTRACT: OBJECTIVE: Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression. METHOD: In a multicenter, double-blind study, adults (ages 18-64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 (SD=12.0) for ketamine and -5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was -17.7 (SD=7.3) for ketamine and -3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, -12.2 [SD=12.8] on day 4; thrice-weekly, -14.0 [SD=12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing. CONCLUSIONS: Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.

8 Clinical Trial Assessment of the Efficacy and Safety of BMS-820836 in Patients With Treatment-Resistant Major Depression: Results From 2 Randomized, Double-Blind Studies. 2015

Bhagwagar, Zubin / Torbeyns, Anne / Hennicken, Delphine / Zheng, Ming / Dunlop, Boadie W / Mathew, Sanjay J / Khan, Arif / Weisler, Richard / Nelson, Craig / Shelton, Richard / Thase, Michael E / Lane, Roger. ·From *Bristol-Myers Squibb Company, Wallingford, CT; †Bristol-Myers Squibb Company, Braine-l'Alleud, Belgium; ‡Emory University, Atlanta, GA; §Baylor College of Medicine, Houston, TX; ∥Northwest Clinical Research Center, Bellevue, WA; ¶Department of Psychiatry, Duke University School of Medicine, Durham; #Department of Psychiatry, Duke University Medical Center, Durham; **Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC; ††University of California, San Francisco, CA; ‡‡University of Alabama at Birmingham, Birmingham, AL; and §§University of Pennsylvania, Philadelphia, PA. ·J Clin Psychopharmacol · Pubmed #25961781.

ABSTRACT: Two phase 2B, randomized, double-blind studies assessed the efficacy and safety of fixed or flexible dose of triple monoamine uptake inhibitor BMS-820836 in patients with treatment-resistant depression to demonstrate whether switching to BMS-820836 was superior to the continuation of standard antidepressant treatment. Patients with a history of inadequate response to 1 to 3 adequate trials of antidepressant therapies were prospectively treated with duloxetine 60 mg/d for 8 weeks (CN162-006) or duloxetine 60 mg/d or escitalopram 20 mg/d for 7 weeks (CN162-007). Inadequate responders were randomized to continue their prospective phase treatment or switch to flexible-dose (0.5-2 mg/d; CN162-006) or fixed-dose (0.25, 0.5, 1, or 2 mg/d; CN162-007) BMS-820836 for 6 weeks. The primary end point in both studies was mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from randomization to study end point. BMS-820836 flexible (0.5-2 mg/d) or fixed dose of 1 mg/d or greater showed efficacy similar to the continuation of antidepressant treatment, with no statistically significant or clinically meaningful differences. In the CN162-006 study, the adjusted mean (SE) change in MADRS total score was -8.7 (0.661) and -8.1 (0.656) for BMS-820836 and duloxetine, respectively (P = 0.526). In the CN162-007 study, the adjusted mean (SE) change in MADRS total score was -7.3 (0.830) and -6.6 (0.842) for BMS-820836 of 1 and 2 mg, respectively, and -6.9 (0.602) for the continuation group (P = 0.910). Thus, BMS-820836 was well tolerated, with no evidence of dose-dependent discontinuations due to adverse events, but it failed to demonstrate superiority to the continuation of an existing antidepressant in patients with treatment-resistant depression.

9 Article Ketamine for acute suicidal ideation. An emergency department intervention: A randomized, double-blind, placebo-controlled, proof-of-concept trial. 2020

Domany, Yoav / Shelton, Richard C / McCullumsmith, Cheryl B. ·Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio. · Department of Psychiatry, Tel Aviv Sourasky Medical Centre, Tel-Aviv, Israel. · Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel. · Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, Alabama. · Department of Psychiatry, College of Medicine and Life Sciences, University of Toledo, Toledo, Ohio. ·Depress Anxiety · Pubmed #31733088.

ABSTRACT: BACKGROUND: Depressed patients presenting to emergency departments with acute suicidal ideation are a major public health concern. Ketamine, a rapidly acting antidepressant with antisuicidal properties, might offer relief. METHODS: In a randomized, double-blind, placebo-controlled, proof-of-concept trial, 18 depressed subjects with acute suicidal ideation, who required hospitalization, were randomized to either an intravenous ketamine 0.2 mg/kg group or a saline placebo group. Safety and efficacy evaluations were scheduled for 15, 30, 60, 90, 120, 180, and 240 min, and on Days 1, 2, 3, 7, and 14 after infusion. The main outcome measure was suicidal ideation with secondary measures of depression. RESULTS: Nine subjects were randomized to each group. There were no differences between groups at baseline in any demographic or assessment scales. A reduction in suicidal ideation was noted at 90-180 min (p < .05). Ninety minutes after infusion, 88% of the ketamine group had achieved remission of suicidal ideation compared with 33% in the placebo group (p < .05). No serious adverse events were noted. CONCLUSIONS: Ketamine was safe and effective for rapid reduction in suicidal ideation in depressed, highly suicidal subjects presenting to the emergency department. Our results support further study of ketamine for acute suicidal ideation.

10 Article Comparing sensitivity to change using the 6-item versus the 17-item Hamilton depression rating scale in the GUIDED randomized controlled trial. 2019

Dunlop, Boadie W / Parikh, Sagar V / Rothschild, Anthony J / Thase, Michael E / DeBattista, Charles / Conway, Charles R / Forester, Brent P / Mondimore, Francis M / Shelton, Richard C / Macaluso, Matthew / Logan, Jennifer / Traxler, Paul / Li, James / Johnson, Holly / Greden, John F. ·Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Dr. NE, 3rd Floor, Atlanta, GA, 30329, USA. bdunlop@emory.edu. · Department of Psychiatry, and National Network of Depression Centers, University of Michigan Comprehensive Depression Center, Ann Arbor, MI, USA. · UMass Memorial Healthcare, University of Massachusetts Medical School, Worcester, MA, USA. · The Corporal Michael Crescenz VAMC, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA. · Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. · Department of Psychiatry, and the John Cochran Veteran's Administration Hospital, Washington University School of Medicine, St. Louis, MO, USA. · McLean Hospital, Division of Geriatric Psychiatry, Harvard Medical School, Belmont, MA, USA. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Psychiatry and School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA. · Department of Psychiatry and Behavioral Sciences, University of Kansas School of Medicine-Wichita, Wichita, KS, USA. · Myriad Genetics, Inc., Salt Lake City, UT, USA. · Assurex Health, Inc./Myriad Neuroscience, Mason, OH, USA. ·BMC Psychiatry · Pubmed #31881956.

ABSTRACT: BACKGROUND: Previous research suggests that the 17-item Hamilton Depression Rating Scale (HAM-D17) is less sensitive in detecting differences between active treatment and placebo for major depressive disorder (MDD) than is the HAM-D6 scale, which focuses on six core depression symptoms. Whether HAM-D6 shows greater sensitivity when comparing two active MDD treatment arms is unknown. METHODS: This post hoc analysis used data from the intent-to-treat (ITT) cohort (N = 1541) of the Genomics Used to Improve DEpression Decisions (GUIDED) trial, a rater- and patient-blinded randomized controlled trial. GUIDED compared combinatorial pharmacogenomics-guided care with treatment as usual (TAU) in patients with MDD. Percent of symptom improvement, response rate and remission rate from baseline to week 8 were evaluated using both scales. Analyses were performed for the full cohort and for the subset of patients who at baseline were taking medications predicted by the test to have moderate or significant gene-drug interactions. A Mokken scale analysis was conducted to compare the homogeneity of HAM-D17 with that of HAM-D6. RESULTS: At week 8, the guided-care arm demonstrated statistically significant benefit over TAU when the HAM-D6 (∆ = 4.4%, p = 0.023) was used as the continuous measure of symptom improvement, but not when using the HAM-D17 (∆ = 3.2%, p = 0.069). Response rates increased significantly for guided-care compared with TAU when evaluated using both HAM-D6 (∆ = 7.0%, p = 0.004) and HAM-D17 (∆ = 6.3%, p = 0.007). Remission rates also were significantly greater for guided-care versus TAU using both measures (HAM-D6 ∆ = 4.6%, p = 0.031; HAM-D17 ∆ = 5.5%, p = 0.005). Patients in the guided-care arm who at baseline were taking medications predicted to have gene-drug interactions showed further increased benefit over TAU at week 8 for symptom improvement (∆ = 7.3%, p = 0.004) response (∆ = 10.0%, p = 0.001) and remission (∆ = 7.9%, p = 0.005) using HAM-D6. All outcomes showed continued improvement through week 24. Mokken scale analysis demonstrated the homogeneity and unidimensionality of HAM-D6, but not of HAM-D17, across treatment arms. CONCLUSIONS: The HAM-D6 scale identified a statistically significant difference in symptom improvement between combinatorial pharmacogenomics-guided care and TAU, whereas the HAM-D17 did not. The demonstrated utility of pharmacogenomics-guided treatment over TAU as detected by the HAM-D6 highlights its value for future biomarker-guided trials comparing active treatment arms. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02109939. Registered 10 April 2014.

11 Article Bipolar depression and suicidal ideation: Moderators and mediators of a complex relationship. 2019

Kamali, Masoud / Reilly-Harrington, Noreen A / Chang, Weilynn C / McInnis, Melvin / McElroy, Susan L / Ketter, Terence A / Shelton, Richard C / Deckersbach, Thilo / Tohen, Mauricio / Kocsis, James H / Calabrese, Joseph R / Gao, Keming / Thase, Michael E / Bowden, Charles L / Kinrys, Gustavo / Bobo, William V / Brody, Benjamin D / Sylvia, Louisa G / Rabideau, Dustin J / Nierenberg, Andrew A. ·Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States; Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States. Electronic address: mkamali@mgh.harvard.edu. · Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States; Harvard Medical School, Boston, MA, United States. · Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States. · Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States. · Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati OH and Lindner Center of HOPE, Mason, OH, United States. · Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States. · Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL, United States. · Department of Psychiatry, University of New Mexico Health Science Center, Albuquerque, NM, United States. · Department of Psychiatry, Weill Cornell Medical College, New York, NY, United States. · Department of Psychiatry, Case Western Reserve University, Cleveland, OH, United States. · Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States. · Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, United States. · Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States. · Department of Biostatistics, Massachusetts General Hospital, Boston, MA, United States. ·J Affect Disord · Pubmed #31445343.

ABSTRACT: INTRODUCTION: Not all patients with bipolar depression have suicidal ideation (SI). This study examines some factors that link bipolar depression to SI. METHODS: 482 individuals with bipolar I or II were randomized to either lithium or quetiapine plus adjunctive personalized therapy in a 24 week comparative effectiveness trial. Severity of depression and SI were assessed with the Bipolar Inventory of Symptoms Scale (BISS). We examined potential moderators (age, gender, age of illness onset, bipolar type, comorbid anxiety, substance use, past suicide attempts, childhood abuse and treatment arm) and mediators (severity of anxiety, mania, irritability, impairment in functioning (LIFE-RIFT) and satisfaction and enjoyment of life (Q-LES-Q)) of the effect of depression on SI. Statistical analyses were conducted using generalized estimating equations with repeated measures. RESULTS: Bipolar type and past suicide attempts moderated the effect of depression on SI. Life satisfaction mediated the effect of depression and SI. The relationship between anxiety, depression and SI was complex due to the high level of correlation. Treatment with lithium or quetiapine did not moderate the effect of depression on SI. LIMITATIONS: Suicide assessment was only done using an item on BISS. Patient population was not specifically chosen for high suicide risk. DISCUSSION: Individuals with Bipolar II experienced more SI with lower levels of depression severity. A history of suicide predisposed patients to higher levels of SI given the same severity of depression. Reduced life satisfaction mediates the effect of depression on SI and may be a target for therapeutic interventions.

12 Article Patterns of changes in bipolar depressive symptoms revealed by trajectory analysis among 482 patients with bipolar disorder. 2019

Behrendt-Møller, Ida / Madsen, Trine / Sørensen, Holger Jelling / Sylvia, Louisa / Friedman, Edward S / Shelton, Richard C / Bowden, Charles L / Calabrese, Joseph R / McElroy, Susan L / Ketter, Terence A / Reilly-Harrington, Noreen A / Gao, Keming / Thase, Michael / V Bobo, William / Tohen, Mauricio / McInnis, Melvin / Kamali, Masoud / Kocsis, James H / Deckersbach, Thilo / Köhler-Forsberg, Ole / Nierenberg, Andrew A. ·Mental Health Centre Copenhagen, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. · Dauten Family Center for Bipolar Treatment Innovation, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts. · Harvard Medical School, Boston, Massachusetts. · Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. · Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama. · Department of Psychiatry, University of Texas Health Science Center, San Antonio, Texas. · Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio. · Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio. · Lindner Center of HOPE, Mason, Ohio. · Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California. · Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Psychiatry & Psychology, Mayo Clinic, Rochester, Minnesota. · Department of Psychiatry, University of New Mexico Health Science Center, Albuquerque, New Mexico. · Department of Psychiatry, University of Michigan, Ann Arbor, Michigan. · Department of Psychiatry, Weill Cornell Medical College, New York, New York. · Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark. ·Bipolar Disord · Pubmed #30383333.

ABSTRACT: INTRODUCTION: Depressive episodes are often prevalent among patients with bipolar disorder, but little is known regarding the differential patterns of development over time. We aimed to determine and characterize trajectories of depressive symptoms among adults with bipolar disorder during 6 months of systematic treatment. METHODS: The pragmatic clinical trial, Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (CHOICE), randomized 482 outpatients with bipolar disorder to lithium or quetiapine. Depressive symptoms were rated at up to 9 visits using the Montgomery-Asberg Depression Rating Scale (MADRS). Growth mixture modeling was utilized to identify trajectories and multinomial regression analysis estimated associations with potential predictors. RESULTS: Four distinct trajectories of depressive symptoms were identified. The responding class (60.3%) with a rapid reduction and subsequent low level; the partial-responding class (18.4%) with an initial reduction followed by an increase during the remaining weeks; the fluctuating class (11.6%) with a fluctuation in depressive symptoms; and the non-responding class (9.7%) with sustained moderate-severe depressive symptoms. Bipolar type I predicted membership of the non-responding class and randomization to quetiapine predicted membership of either the responding or the non-responding class. CONCLUSION: Approximately 30% experienced a partial or fluctuating course, and almost 10% had a chronic course with moderate-severe depression during 6 months. Patients diagnosed with bipolar type 1 had higher risk of being categorized into a class with a worse outcome. While no differences in average overall outcomes occurred between the lithium and quetiapine groups, trajectory analysis revealed that the lithium group had more variable courses.

13 Article Major Depressive Disorder Following Dermatomyositis: A Case Linking Depression with Inflammation. 2018

Reddy, Abhishek / Birur, Badari / Shelton, Richard C / Li, Li. ·Reddy, MD, Birur, MD, Shelton, MD, Li, MD, Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, AL, 35294. ·Psychopharmacol Bull · Pubmed #29713102.

ABSTRACT: Major depressive disorder (MDD) is one of the most common psychiatric disorders. Recent studies have shown a strong association between MDD and peripheral inflammation, shown by a higher incidence of depression in patients with inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and systemic lupus erythematosus. Dermatomyositis (DM), an idiopathic inflammatory connective tissue disease that is associated with inflammation, predominantly affects the skin and skeletal muscle. The association between DM and MDD in the context of inflammation has seldom been reported. Here we report a 30- year- old Caucasian female with symptoms of depression dating back to 2 years. These symptoms started after cutaneous manifestations of DM. In the past two years, her DM symptoms have worsened that paralleled an increase of depressive symptoms. Also, during the course of the patient's DM, we tracked elevated inflammatory markers including creatine kinase and aldolase, whereas C-reactive protein, C3, and C4 were in a high normal range which correlated with worsening of depression. Hence, a temporal relationship between the onset of MDD and DM symptoms suggests that inflammation may be a common mechanism linking these two conditions.

14 Article Role of Complex Epigenetic Switching in Tumor Necrosis Factor-α Upregulation in the Prefrontal Cortex of Suicide Subjects. 2018

Wang, Qingzhong / Roy, Bhaskar / Turecki, Gustavo / Shelton, Richard C / Dwivedi, Yogesh. ·From the Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham; and the Department of Psychiatry, McGill University, Montreal, Canada. ·Am J Psychiatry · Pubmed #29361849.

ABSTRACT: OBJECTIVE: Proinflammatory cytokines have recently received considerable attention for their role in suicidal behavior; however, how the expression of cytokine genes is regulated is not clearly known. The authors examined underlying mechanisms of critical cytokine gene tumor necrosis factor-alpha (TNF-α) dysregulation in the brains of individuals who died by suicide. METHOD: TNF-α expression was examined in the dorsolateral prefrontal cortex of the postmortem brains of persons with and without major depressive disorder who died by suicide and of persons with major depressive disorder who died of causes other than suicide. The role of putative microRNAs targeting TNF-α and RNA-binding protein Hu antigen R (HuR) was tested with in vitro and in vivo approaches and by examining expression of transactivation response RNA binding protein (TRBP). Genetic influence on TNF-α expression was determined by expression quantitative trait loci analysis and by genotyping three single-nucleotide polymorphisms in the promoter region of the TNF-α gene. Promoter methylation of TNF-α was determined by using methylated DNA immunoprecipitation assay. Expression of miR-19a-3p and TNF-α was also determined in the peripheral blood mononuclear cells of 12 healthy control subjects and 12 currently depressed patients with severe suicidal ideation. RESULTS: TNF-α expression was significantly higher in the dorsolateral prefrontal cortex of individuals who died by suicide, regardless of psychiatric diagnosis. Its expression level was also increased in individuals with major depressive disorder who died by causes other than suicide. On the other hand, expression of miR-19a-3p was upregulated specifically in individuals who died by suicide. In a preliminary observation, similar upregulation of TNF-α and miR-19a-3p was observed in the peripheral blood mononuclear cells of depressed patients with suicidal ideation. Despite its ability to directly target TNF-α in vitro, miR-19a-3p showed no interaction with TNF-α in the dorsolateral prefrontal cortex. HuR potentially stabilized TNF-α transcript, presumably by sequestering its 3' untranslated region from miR-19a-3p-mediated inhibition. Furthermore, decreased TRBP expression supported abnormality in the interaction between miR-19a-3p and TNF-α. Additionally, TNF-α transcriptional upregulation was associated with promoter hypomethylation, whereas no genetic influence on altered TNF-α or miR-19a-3p expression was observed in individuals who died by suicide. CONCLUSIONS: The data in this study provide mechanistic insights into the dysregulation of the TNF-α gene in the brains of individuals who died by suicide, which could potentially be involved in suicidal behavior.

15 Article Treatment outcomes of acute bipolar depressive episode with psychosis. 2018

Caldieraro, Marco Antonio / Dufour, Steven / Sylvia, Louisa G / Gao, Keming / Ketter, Terence A / Bobo, William V / Walsh, Samantha / Janos, Jessica / Tohen, Mauricio / Reilly-Harrington, Noreen A / McElroy, Susan L / Shelton, Richard C / Bowden, Charles L / Deckersbach, Thilo / Nierenberg, Andrew A. ·Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. · Serviço de Psiquiatria, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil. · Harvard Medical School, Boston, MA, USA. · Mood Disorders Program, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA. · Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. · Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA. · Department of Psychiatry & Behavioral Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. · Lindner Center of HOPE, Mason, OH, USA. · Deparment of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH, USA. · University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA. ·Depress Anxiety · Pubmed #29329498.

ABSTRACT: BACKGROUND: The impact of psychosis on the treatment of bipolar depression is remarkably understudied. The primary aim of this study was to compare treatment outcomes of bipolar depressed individuals with and without psychosis. The secondary aim was to compare the effect of lithium and quetiapine, each with adjunctive personalized treatments (APTs), in the psychotic subgroup. METHODS: We assessed participants with DSM-IV bipolar depression included in a comparative effectiveness study of lithium and quetiapine with APTs (the Bipolar CHOICE study). Severity was assessed by the Bipolar Inventory of Symptoms Scale (BISS) and by the Clinical Global Impression Scale-Severity-Bipolar Version (CGI-S-BP). Mixed models were used to assess the course of symptom change, and Cox regression survival analysis was used to assess the time to remission. RESULTS: Psychotic features were present in 10.6% (n = 32) of the depressed participants (n = 303). Those with psychotic features had higher scores on the BISS before (75.2 ± 17.6 vs. 54.9 ± 16.3; P < .001) and after (37.2 ± 19.7 vs. 26.3 ± 18.0; P = .003) 6-month treatment. The CGI-S-BP yielded similar results. Participants with and without psychosis had similar course of symptom improvement and similar time to remission. There was no significant difference in the treatment outcomes of lithium (n = 11) and quetiapine (n = 21) among the psychotic subgroup. CONCLUSION: Bipolar depressive episodes with psychotic features are more severe, and compared to nonpsychotic depressions, present a similar course of improvement. Given the small number of participants presenting psychosis, the lack of statistically significant difference between lithium- and quetiapine-based treatment of psychotic bipolar depressive episodes needs replication in a larger sample.

16 Article Decreased activation and subsyndromal manic symptoms predict lower remission rates in bipolar depression. 2018

Caldieraro, Marco Antonio / Walsh, Samantha / Deckersbach, Thilo / Bobo, William V / Gao, Keming / Ketter, Terence A / Shelton, Richard C / Reilly-Harrington, Noreen A / Tohen, Mauricio / Calabrese, Joseph R / Thase, Michael E / Kocsis, James H / Sylvia, Louisa G / Nierenberg, Andrew A. ·1 Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. · 2 Serviço de Psiquiatria, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. · 3 Harvard Medical School, Boston, MA, USA. · 4 Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA. · 5 Mood Disorders Program, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA. · 6 Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. · 7 The University of Alabama at Birmingham, Birmingham, AL, USA. · 8 Department of Psychiatry and Behavioral Sciences, UNM Health Sciences Center, The University of New Mexico, Albuquerque, NM, USA. · 9 Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · 10 Department of Psychiatry, Weill Cornell Medical College, Ithaca, NY, USA. ·Aust N Z J Psychiatry · Pubmed #29143534.

ABSTRACT: OBJECTIVE: Activation encompasses energy and activity and is a central feature of bipolar disorder. However, the impact of activation on treatment response of bipolar depression requires further exploration. The aims of this study were to assess the association of decreased activation and sustained remission in bipolar depression and test for factors that could affect this association. METHODS: We assessed participants with Diagnostic and Statistical Manual of Mental Disorders (4th ed) bipolar depression ( n = 303) included in a comparative effectiveness study of lithium- and quetiapine-based treatments (the Bipolar CHOICE study). Activation was evaluated using items from the Bipolar Inventory of Symptoms Scale. The selection of these items was based on a dimension of energy and interest symptoms associated with poorer treatment response in major depression. RESULTS: Decreased activation was associated with lower remission rates in the raw analyses and in a logistic regression model adjusted for baseline severity and subsyndromal manic symptoms (odds ratio = 0.899; p = 0.015). The manic features also predicted lower remission (odds ratio = 0.934; p < 0.001). Remission rates were similar in the two treatment groups. CONCLUSION: Decreased activation and subsyndromal manic symptoms predict lower remission rates in bipolar depression. Patients with these features may require specific treatment approaches, but new studies are necessary to identify treatments that could improve outcomes in this population.

17 Article Double-blind, proof-of-concept (POC) trial of Low-Field Magnetic Stimulation (LFMS) augmentation of antidepressant therapy in treatment-resistant depression (TRD). 2018

Fava, Maurizio / Freeman, Marlene P / Flynn, Martina / Hoeppner, Bettina B / Shelton, Richard / Iosifescu, Dan V / Murrough, James W / Mischoulon, David / Cusin, Cristina / Rapaport, Mark / Dunlop, Boadie W / Trivedi, Madhukar H / Jha, Manish / Sanacora, Gerard / Hermes, Gretchen / Papakostas, George I. ·Massachusetts General Hospital, United States. Electronic address: mfava@mgh.harvard.edu. · Massachusetts General Hospital, United States. · University of Alabama at Birmingham, United States. · Icahn School of Medicine at Mount Sinai, United States. · Emory University, United States. · University of Texas Southwestern, United States. · Yale University, United States. ·Brain Stimul · Pubmed #29030111.

ABSTRACT: BACKGROUND: Low-Field Magnetic Stimulation (LFMS) is a novel, non-invasive, sub-threshold neuromodulation technique, shown in preliminary studies to have immediate mood elevating effects in both unipolar and bipolar depressed patients. OBJECTIVE: We aimed to assess the antidepressant augmentation effects at 48 h of LFMS administered on two consecutive days compared to sham treatment in treatment resistant depression (TRD) subjects, using the Sequential Parallel Comparison Design (SPCD). METHODS: Eighty-four eligible subjects with TRD were randomly assigned to double-blind treatment with LFMS 20 min/day for four days, sham treatment 20 min/day for four days, or sham treatment 20 min/day for 2 days followed by LFMS treatment 20 min/day for two days, using the pre-randomization version of the SPCD (randomization 1:1:1). The SPCD analyses used a repeated measures linear modeling approach with maximum likelihood estimation to use all available data, and using a 60-40 weighting of Stage 1 vs. 2 responses, with the primary outcome being measured after 2 and 4 days. RESULTS: Both primary and secondary outcome measures consistently showed no differences between LFMS-treated patients and those treated with sham, with the exception of a slight, non-significantly greater improvement than sham in the visual analogue scale (VAS) sad mood on LFMS-treated patients. LFMS treatment was relatively well tolerated. CONCLUSIONS: We did not observe a significantly greater, rapid efficacy of LFMS compared to sham therapy. Future studies need to examine the possible therapeutic effects of more intensive forms of LFMS, as other forms of neurostimulation typically require longer duration of exposure.

18 Article Efficacy of Ziprasidone Augmentation of Escitalopram for Cognitive Symptoms of Major Depressive Disorder. 2018

Iovieno, Nadia / Shelton, Richard C / Petrie, Samuel R / Cusin, Cristina / Fava, Maurizio / Papakostas, George I. ·Clinical Trials Network and Institute, Massachusetts General Hospital, One Bowdoin Square, Boston, MA 02114. niovieno@partners.org. · Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, Massachusetts, USA. · University of Alabama-Birmingham Department of Psychiatry and Behavioral Neurobiology, Birmingham, Alabama, USA. · Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. ·J Clin Psychiatry · Pubmed #28749091.

ABSTRACT: OBJECTIVE: To examine the efficacy of adjunctive ziprasidone for cognitive symptoms in adult patients with major depressive disorder (MDD) experiencing persistent symptoms after 8 weeks of open-label escitalopram. METHODS: This post hoc analysis was conducted on a database derived from a previously published study. The parent study was a multicenter, parallel, randomized, double-blind, placebo-controlled trial conducted at 3 academic medical centers in the United States from July 2008 to October 2013. The participant pool consisted of 139 outpatients with persistent symptoms of MDD, according to DSM-IV criteria, following an 8-week open label, flexible-dose trial of escitalopram. Subjects were randomly assigned (1:1, N = 139) to adjunctive fixed-dose ziprasidone (escitalopram + ziprasidone, n = 71) or adjunctive placebo (escitalopram + placebo, n = 68) with 8 weekly follow-up assessments. Primary outcome was clinical response according to the 17-item Hamilton Depression Rating Scale, which was defined as a 50% or greater reduction in scale scores. The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) was used to measure cognitive and executive dysfunction at each study visit. All statistical testing was conducted at the nominal, 2-sided, 0.05 level of significance. RESULTS: Adjunctive ziprasidone therapy did not result in significantly greater improvement in CPFQ scores compared to adjunctive placebo (P > .05). Residual cognitive symptoms were reported in a substantial number of patients who were considered responders to either adjunctive ziprasidone or placebo. CONCLUSIONS: In the present study, ziprasidone used adjunctively with the selective serotonin reuptake inhibitor escitalopram did not demonstrate a greater efficacy for cognitive symptoms in patients with MDD compared with adjunctive placebo. Future, well-designed studies examining the role of atypical antipsychotics or other augmentation versus switch strategies for cognitive symptoms in MDD are warranted.

19 Article Clinical and Genetic Predictors of Delayed Remission After Multiple Levels of Antidepressant Treatment: Toward Early Identification of Depressed Individuals for Advanced Care Options. 2017

Falola, Michael I / Limdi, Nita / Shelton, Richard C. ·SC 925, 1720 2nd Ave South, Birmingham, AL 35294-0017. mfalola@uabmc.edu. · Department of Psychiatry, The University of Alabama, Birmingham, Alabama, USA. · Department of Neurology, The University of Alabama, Birmingham, Alabama, USA. ·J Clin Psychiatry · Pubmed #29178685.

ABSTRACT: OBJECTIVE: To identify clinical and genetic characteristics that can be used to recognize depressed patients who are likely to respond quickly versus those who will have a more delayed response following multiple treatment trials. METHODS: The data used were obtained from the National Institute of Mental Health-sponsored Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which was conducted between July 2001 and September 2006. Of the 4,041 treatment-naive participants in the original study, 1,953 with DNA samples were included. Major depressive disorder (DSM-IV criteria) was defined as baseline score > 14 on the 17-item Hamilton Depression Rating Scale. Time to remission was defined from the entry point to when a score ≤ 5 on the Quick Inventory of Depressive Symptomatology, Clinician Rating was achieved, irrespective of the type or number of treatments received. A Kaplan-Meier estimator was used for data description, proportional hazard regression for model building, and logistic regression for measures of predictive accuracy. RESULTS: The overall rate of remission across all levels of treatment was 65.6%, and the overall median (interquartile range) of time to remission was 11.4 (6.0-17.9) weeks. The predictors of delayed remission included unemployment (P = .004), severe medical comorbidity (P < .0001), severe baseline depression (P < .0001), more than 4 dysthymic symptoms (P = .005), more than 9 posttraumatic stress symptoms (P = .005), and serotonin receptor 1A (P = .006) and cytochrome P450 2D6 (P = .002 for C/T and P = .0004 for T/T) genetic variants. The final model had good predictive measures of accuracy of area under the curve (70%) and sensitivity (88%). CONCLUSIONS: The results offer clinical tools for clinicians to identify depressed individuals who are likely to have delayed remission with multiple antidepressant treatments and therefore might be candidates for advanced care options.

20 Article Gender-Specific Relationship between Obesity and Major Depression. 2017

Li, Li / Gower, Barbara A / Shelton, Richard C / Wu, Xiaoyan. ·Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States. · Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, United States. · Department of Nephrology, Wuhan University, Wuhan, China. ·Front Endocrinol (Lausanne) · Pubmed #29176959.

ABSTRACT: Objective: Prior research suggests a bidirectional relationship between obesity and major depressive disorder (MDD), but the results have been heterogeneous. Differences between males and females in the association of MDD with obesity may contribute to inconsistent results. Thus, this study was designed to determine whether sex has a differential effect on the relationship between MDD and obesity, and to explore the potential mechanisms. Methods: All participants were diagnosed with MDD, and depression severity was measured using the 17-item Hamilton Depression Rating Scale. Body weight and height were measured to calculate body mass index (BMI). Body composition, including total fat, trunk fat, android fat, and visceral fat mass, was measured by dual-energy X-ray absorptiometry. Subjects provided blood samples, and serum was extracted for measuring the inflammatory factors using human immunoassay kits. Results: Among all obesity measures, depressed women had greater BMI and total body fat. By contrast, depressed men had greater visceral fat mass. However, only in depressed women was depression correlated with several measures of obesity, including BMI, total body fat, and visceral fat mass. A stepwise multiple regression analysis was conducted, and only visceral fat entered the regression model and was most predictive of depression in women (β = 0.60, Conclusion: These results highlight gender differences in determining the association between obesity and depression, and elevated leptin level is a potential mechanism linking MDD to obesity in depressed women. Understanding a gender-specific relationship between obesity and MDD would allow clinicians to target and personalize therapies in the hope of improving health outcomes.

21 Article Response to: Commentary: Sex Differences in the Peripheral Immune System in Patients with Depression. 2017

Birur, Badari / Shelton, Richard C / Amrock, Ellen M / Li, Li. ·Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States. · Birmingham VA Medical Center (VHA), Birmingham, AL, United States. ·Front Psychiatry · Pubmed #29176954.

ABSTRACT: -- No abstract --

22 Article Sex Differences in the Peripheral Immune System in Patients with Depression. 2017

Birur, Badari / Amrock, Ellen M / Shelton, Richard C / Li, Li. ·Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States. ·Front Psychiatry · Pubmed #28670290.

ABSTRACT: BACKGROUND: Females are twice as likely as males to experience depression. Recent findings indicate a relationship linking inflammation with depression. Whether the higher prevalence of depression in women is sex-specific or if inflammation contributes to a higher prevalence of depression in females is unclear. Thus, the objective was to determine whether depressed females show higher inflammation compared to males in a cross-sectional study. MATERIALS AND METHODS: Two hundred participants were enrolled. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS), and blood samples were collected from all participants to measure inflammatory blood markers. RESULTS: Higher rates of suicidal thoughts, pessimism, and lassitude measured by the MADRS were seen in depressed females compared with depressed males. Among all inflammatory markers measured, there were no significant differences in depressed males vs. male controls. Increased levels of interleukin (IL)-8, interferon-γ, and leptin, and decreased levels of IL-5 and adiponectin were observed in depressed females compared to female controls. Compared with depressed males, IL-6 and leptin levels were significantly elevated in depressed females after controlling for body mass index. Correlation analysis revealed that depression severity negatively correlated with IL-12 in males, and positively correlated with IL-1β and tumor necrosis factor (TNF)-α in females. IL-1β and TNF-α correlated with suicidal thoughts, lassitude, and pessimism in depressed females. CONCLUSION: Our findings indicate a sex-specific relationship between inflammation and depression, which may be important in identifying potential psychopathology and suggesting novel immunomodulatory treatments for depressed females.

23 Article Bipolar mixed features - Results from the comparative effectiveness for bipolar disorder (Bipolar CHOICE) study. 2017

Tohen, Mauricio / Gold, Alexandra K / Sylvia, Louisa G / Montana, Rebecca E / McElroy, Susan L / Thase, Michael E / Rabideau, Dustin J / Nierenberg, Andrew A / Reilly-Harrington, Noreen A / Friedman, Edward S / Shelton, Richard C / Bowden, Charles L / Singh, Vivek / Deckersbach, Thilo / Ketter, Terence A / Calabrese, Joseph R / Bobo, William V / McInnis, Melvin G. ·Department of Psychiatry & Behavioral Sciences, University of New Mexico, Health Sciences Center, Albuquerque, NM, USA. Electronic address: mtohen@salud.unm.edu. · Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. · Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. · Lindner Center of HOPE, Mason, OH, USA; Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH, USA. · Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA. · University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL, USA. · Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA. · Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. · Bipolar Disorders Research Center, University Hospital's Case Medical Center, Case Western Reserve University, Cleveland, OH, USA. · Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA. · Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA. ·J Affect Disord · Pubmed #28411507.

ABSTRACT: BACKGROUND: DSM-5 changed the criteria from DSM-IV for mixed features in mood disorder episodes to include non-overlapping symptoms of depression and hypomania/mania. It is unknown if, by changing these criteria, the same group would qualify for mixed features. We assessed how those meeting DSM-5 criteria for mixed features compare to those meeting DSM-IV criteria. METHODS: We analyzed data from 482 adult bipolar patients in Bipolar CHOICE, a randomized comparative effectiveness trial. Bipolar diagnoses were confirmed through the MINI International Neuropsychiatric Interview (MINI). Presence and severity of mood symptoms were collected with the Bipolar Inventory of Symptoms Scale (BISS) and linked to DSM-5 and DSM-IV mixed features criteria. Baseline demographics and clinical variables were compared between mood episode groups using ANOVA for continuous variables and chi-square tests for categorical variables. RESULTS: At baseline, the frequency of DSM-IV mixed episodes diagnoses obtained with the MINI was 17% and with the BISS was 20%. Using DSM-5 criteria, 9% of participants met criteria for hypomania/mania with mixed features and 12% met criteria for a depressive episode with mixed features. Symptom severity was also associated with increased mixed features with a high rate of mixed features in patients with mania/hypomania (63.8%) relative to those with depression (8.0%). LIMITATIONS: Data on mixed features were collected at baseline only and thus do not reflect potential patterns in mixed features within this sample across the study duration. CONCLUSIONS: The DSM-5 narrower, non-overlapping definition of mixed episodes resulted in fewer patients who met mixed criteria compared to DSM-IV.

24 Article Clinical correlates of acute bipolar depressive episode with psychosis. 2017

Caldieraro, Marco Antonio / Sylvia, Louisa G / Dufour, Steven / Walsh, Samantha / Janos, Jessica / Rabideau, Dustin J / Kamali, Masoud / McInnis, Melvin G / Bobo, William V / Friedman, Edward S / Gao, Keming / Tohen, Mauricio / Reilly-Harrington, Noreen A / Ketter, Terence A / Calabrese, Joseph R / McElroy, Susan L / Thase, Michael E / Shelton, Richard C / Bowden, Charles L / Kocsis, James H / Deckersbach, Thilo / Nierenberg, Andrew A. ·Serviço de Psiquiatria, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Electronic address: mcaldieraro@hcpa.edu.br. · Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. · Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. · Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA. · Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA. · Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA. · University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Mood Disorders Program, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA. · Department of Psychiatry & Behavioral Sciences, University of New Mexico Health Sciences Center, Albuquerque, NM, USA. · Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA USA. · Lindner Center of HOPE, Mason, OH, USA; Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH, USA. · Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Department of Psychiatry, University of Texas Health Science Center, San Antonio, TX, USA. · Department of Psychiatry, Weill Cornell Medical College, Ithaca, NY, USA. ·J Affect Disord · Pubmed #28365478.

ABSTRACT: BACKGROUND: Psychotic bipolar depressive episodes remain remarkably understudied despite being common and having a significant impact on bipolar disorder. The aim of this study is to identify the characteristics of depressed bipolar patients with current psychosis compared to those without psychosis. METHODS: We used baseline data of a comparative effectiveness study of lithium and quetiapine for bipolar disorder (the Bipolar CHOICE study) to compare demographic, clinical, and functioning variables between those with and without psychotic symptoms. Of the 482 participants, 303 (62.9%) were eligible for the present study by meeting DSM-IV criteria for an acute bipolar depressive episode. Univariate analyses were conducted first, and then included in a model controlling for symptom severity. RESULTS: The sample was composed mostly of women (60.7%) and the mean age was 39.5±12.1 years. Psychosis was present in 10.6% (n=32) of the depressed patients. Psychotic patients had less education, lower income, and were more frequently single and unemployed. Psychosis was also associated with a more severe depressive episode, higher suicidality, more comorbid conditions and worse functioning. Most group differences disappeared when controlling for depression severity. LIMITATIONS: Only outpatients were included and the presence of psychosis in previous episodes was not assessed. CONCLUSION: Psychosis during bipolar depressive episodes is present even in an outpatient sample. Psychotic, depressed patients have worse illness outcomes, but future research is necessary to confirm if these outcomes are only associated with the severity of the disorder or if some of them are independent of it.

25 Article DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation. 2017

Roy, Bhaskar / Shelton, Richard C / Dwivedi, Yogesh. ·Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: ydwivedi@uab.edu. ·J Psychiatr Res · Pubmed #28246044.

ABSTRACT: Stress plays an important role in major depressive disorder (MDD) and is one of the state dependent factors in suicidal behavior. A dysfunctional hypothalamic-pituitary-adrenal axis is a common feature in this disorder. The involvement of environmental factors has added additional complexity to understanding depression or suicidal behavior. In this regard, epigenetic regulation has been considered a mechanistic interface between environmental stress stimuli and altered functioning of underlying gene network that may increase susceptibility to depression or suicidal behavior. The present study examined whether epigenetic modifications of stress related genes are associated with MDD and whether there are differences in these epigenetic marks between depressed individuals with and without serious suicidal ideation. Using MeDIP analysis in genomic DNA isolated from peripheral blood mononuclear cells (PBMC) of healthy controls (n = 20), MDD patients with (n = 14) or without serious suicidal ideation (n = 10), we studied methylation of the stress-associated genes, Brain Derived Neurotrophic Factor (BDNF), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), FK506 Binding Protein 5 (FKBP5), Corticotropin Releasing Hormone Binding Protein (CRHBP), and Corticotropin Releasing Hormone Receptor 1 (CRHR1). In addition, we determined their transcript levels in RNAs isolated from the same PBMC. We found that BDNF, FKBP5, CRHBP, and NR3C1 gene promoters were significantly hypermethylated in MDD patients with and without suicidal ideation. We also found concomitant reductions in expression of BDNF, FKBP5 transcript variants (1, 2 and 3), and NR3C1 genes in these patients, suggesting that promoter hypermethylation in these genes may functionally be associated with their observed downregulation in MDD patients. In a secondary analysis, methylation of these genes was compared between MDD patients with or without serious suicidal ideation and controls. The MDD with serious suicidal ideation were significantly different from controls while the MDD without were not, although MDD with or without suicidal ideation were not different from each other, likely owning to a relatively small sample size. Thus, our findings underline the importance of epigenetic modifications of stress-associated genes in depression and, possibly, suicidal behavior, which, in future, needs to be confirmed in a larger patient population.

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